Chapter 13: Behavior of Chemical and Slow Voltage-Sensitive Gates of Connexin Channels: The “Cork” Gating Hypothesis

Abstract

The permeability of gap junction channels to small cytosolic molecules is finely regulated by specific changes in cytosolic ionic composition. As gap junction channels close, cells uncouple from each other electrically and metabolically. Uncoupling is primarily a protective mechanism that enables healthy cells to isolate themselves from damaged neighbors, but evidence for channel gating sensitivity to nearly physiological calcium and hydrogen ion concentrations suggests that gap junction permeability modulation may play a role in normal cellular functions as well. Identifying the uncoupling agents and the molecular basis of channel gating is essential for understanding how cell communication is physiologically controlled and how cell coupling relates to specific cellular activities. Mechanism of channel gating can only be understood once a thorough knowledge of connexin domains relevant to gating and of cytosolic participants in gating processes is achieved. This chapter discusses the current knowledge of gap junction regulation by cytosolic acidification, focusing on molecular domains of connexins believed to participate in channel gating. Much of the material deals with gap junction channels made of connexin32 (Cx32), a connexin expressed widely in the mammalian tissues such as liver, pancreas, kidney, nervous system, thyroid, and mammary gland, and whose genetic mutation is involved in the pathogenesis of the X-linked Charcot-Marie-Tooth (CMTX) demyelinating disease.